Diagnostic algorithm to reduce TB deaths in HIV patients

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The World Health Organisation released a new diagnostic algorithm to reduce the likelihood of ‘seriously ill’ people with HIV dying of undiagnosed and untreated tuberculosis.

“Despite being preventable and curable TB is still the leading cause of morbidity and mortality, even in the era of antiretroviral therapy (ART) going to scale. In fact, in 2014, it accounted for nearly a third of HIV-related deaths,” said Dr Annabel Baddeley, of WHO’s Global TB Programme, who moderated a session at the 21st International AIDS Conference (AIDS 2016) in Durban, South Africa dedicated to discussing the need, evidence base and application of the algorithm and other strategies to reduce mortality from HIV-associated TB.

Although people living with HIV are being started on treatment earlier – data from some large cohorts show that the median CD4 cell count at treatment initiation has doubled – the proportion of people who present for care with very advanced disease has remained relatively unchanged and “mortality is largely, in most parts of the world, due to the same problems,” said Dr Nathan Ford of the WHO, who presented more data on the enduring burden of TB morbidity and mortality among people living with HIV.

A systematic review carried out by Ford and colleagues found that Aids-defining illnesses continue to be the leading cause of hospitalisation in people living with HIV, and around one in five of those people are hospitalised due to TB.

Importantly, 30% of people living with HIV who were hospitalised were only diagnosed with HIV at the time of hospitalisation – underscoring the challenge of reaching people living with HIV earlier in the course of infection. The median CD4 cell count at diagnosis was 131. Another systematic review which looked at post-mortem data on the cause of death, found that in resource-limited settings, TB accounts for approximately 40% of facility-based HIV/Aids-related adult deaths (43.2% in sub-Saharan Africa and 63.2% in Southeast Asia) (Gupta 2015).

But the ‘late presenters’ are not the only ones at risk of being hospitalised with advanced HIV disease and TB. A South African study of medical admissions found that more than a third (35.7%) of the people living with HIV admitted to a public sector district hospital in Cape Town had not yet started ART, 45% reported being currently on ART, while another 19.3% reported that they had initiated therapy but, for one reason or another, had interrupted care. Again, the most frequent primary diagnosis was TB (33.5%). Outcomes among the cohort were poor – within 90 days of follow-up, 29.9% required readmission and 13.3% had died. TB was the most common cause of death (in 37.2%) (Meintjes 2015).

Case fatality rates among people being treated for TB are more than three times greater if they are HIV-positive than if they are HIV-negative – and even higher if they are not put on ART as soon as possible after starting TB treatment. But according to Ford, it often does not happen.

“It’s indicative of the need in the TB community and in the TB/HIV community to do a much better job at ascertaining gaps in the cascade of care, and where we need to focus our attention in the continuum from diagnosis to long-term treatment success,” he said. “There are major challenges in diagnosing HIV among those who are TB-positive, and major challenges in putting HIV/TB co-infected individuals on ART despite many, many years of of recommending immediate ART in all patients who are TB co-infected.”

WHO has long recognised the need to respond more effectively to prevent deaths from undiagnosed TB in HIV-positive people. In effect, the new algorithm is descended from the algorithm for diagnosis of smear-negative TB in HIV-prevalent settings, only updated in light of the latest technology and data on presumptive treatment – and targeted to the most seriously ill people with HIV at greatest risk of dying of TB.

The reasons why TB can be difficult to diagnose in people with advanced HIV disease have changed little, even with current tests: people living with HIV are often unable to provide sufficient and high quality sputum specimens for lab tests; even when they can produce sputum, the amount of TB bacilli in the specimen may be very low; also people with HIV have high rates of extrapulmonary TB.

The new algorithm is specifically designed to provide earlier access to TB treatment to the most seriously ill people with HIV or of unknown HIV status in resource-limited settings – particularly peripheral settings where access to TB diagnostics is limited.

If a person with HIV or unknown HIV status visits a peripheral health facility – such as a primary health clinic or outpost – and is suspected of having TB and has danger signs, they should be immediately referred to a higher level medical facility if possible.

Often referral is not possible, and in those cases, the algorithm recommends performing an Xpert MTB/RIF test and a lateral flow LAM test (according to the guidelines mentioned above). Meanwhile, the individual should be given intravenous antibiotics to treat any possible bacterial infections, and treatment for Pneumocystis pneumonia should also be considered. If available, a chest x-ray should be performed to help guide the clinician’s decision.

If any of the TB tests come back positive, TB treatment should be initiated, but if the TB tests are negative or not available, then: if there is improvement of symptoms after 3-5 days, TB is unlikely, and the care provider should look for other HIV-related diseases, consider starting ART as soon as possible, provide isoniazid preventive therapy and cotrimoxazole preventive therapy and complete the course of parenteral antibiotics.

But if there is no improvement or symptoms worsen after three to five days, presumptive TB treatment should be started, as well as ART and cotrimoxazole preventive therapy. The clinician should perform further investigations for TB (such as culture) and other diseases and complete the course of parenteral antibiotics.

Yohhei Hamada of WHO’s Global TB Programme, who presented the new algorithm, noted that there are some tools (or approaches) that can help to expedite TB diagnosis and treatment.

The Xpert MTB/RIF is much more sensitive than smear microscopy (manually looking for bacilli in a treated sputum sample under a microscope), detecting up to 79% of pulmonary TB in people living with HIV (a future generation of the test, ‘the Ultra’ promises even higher sensitivity). In addition, the test is automated and can generate a result in less than two hours.

WHO recommends that Xpert MTB/RIF, “should be used as the initial diagnostic test in people living with HIV to diagnose pulmonary TB and TB meningitis,” said Hamada. It may also be used rather than conventional tests (culture) for testing other extra-pulmonary specimens (from lymph nodes and other tissues).
However, even though the cost of the Xpert MTB/RIF test cartridges has been brought down, the equipment that runs the test is expensive, severely limiting access to the tests in many resource-limited settings.

Furthermore, in most countries where the test has been scaled up, such as South Africa, it is primarily performed at district or regional laboratories – meaning that specimens must usually be transported from the primary health care clinic to the lab, and the results then sent back to the clinic – which must then track down the patient.

Another tool that can speed up TB diagnosis in some of the most ill individuals, the LAM assay, is a urine-based test that can routinely be used at point-of-care, generating results in 25 minutes. Unfortunately, the sensitivity of the test is limited in people who aren’t in the hospital or who have CD4 cells higher than 200. However, WHO reviewed the available literature and found that in five studies, the pooled sensitivity of the LAM assay for TB in people with CD4 cell counts of 100 or less was 56% and 49% in those with CD4 counts of 200 or less, while in six studies, the pooled sensitivity for TB in hospital inpatients was 54%.

Consequently, WHO recommends that the lateral flow LAM test should be only used to assist in the diagnosis of active TB in HIV-positive adults and children (both in- and out-patients), presumed to have TB, who: have a CD4 cell count of 100 or below, or are seriously ill (see definition above), regardless of CD4 cell count. The LAM should not be used as a screening test for TB, however.

Finally, in certain cases, WHO recommends presumptively treating suspected TB, which it defines as the “initiation of TB treatment for people living with HIV in peripheral facilities, based exclusively on clinical suspicion [of TB in] ‘seriously ill patients’ with respiratory distress based on the judgment of the clinician.”

Several recently reported trials of empiric or presumptive TB treatment have failed to show benefit – however, Hamada stressed that the protocols did not meet WHO’s definition of presumptive treatment and, in particular, were not targeted to individuals meeting the algorithm’s definition of seriously ill, which includes any individual with HIV or of unknown HIV status presenting with one or more of the following danger signs: unable to walk unaided; a respiratory rate over 30/min; a fever of more than 39oC; and/or a pulse rate of over 120/min.

The first of these studies was the REMEMBER trial which found no benefit providing empirical TB treatment over providing isoniazid preventive therapy (IPT) to people living with HIV with less than 50 CD4 cells. However, Hamada pointed out that the study only included participants in whom TB had been ruled out by extensive investigations and was therefore not suspected.

A more recent study, the TB Fast Track Trial, did evaluate empiric treatment in individuals with CD4 cell counts of 150 or below, who were suspected of having TB (a positive LAM test and/or low haemoglobin or body mass indexes). Indeed, those considered to have a high probability of TB were more likely to receive an eventual confirmed TB diagnosis (in 11.5%), but there was no significant benefit to empiric treatment. This may have been due to the fact, that in practice and contrary to expectations, empiric TB treatment was also associated with delayed ART initiation. A closer look at the data found that delayed ART was linked to poorer outcomes – one must remember that ART was delayed in the majority of those put on empiric TB treatment who did not in fact have TB). This underscores the need to not delay ART treatment in people provided with empiric TB treatment no matter what the protocol – and that it may be important to limit presumptive TB treatment to those at the highest risk of having TB.

Note, all the participants in the TB Fast Track Trial were ambulatory, and they were not required to have any of the other danger signs.

The failure of these particular empiric therapy strategies to improve survival does not mean other presumptive TB treatment will not work. In fact, in a recently published study, empiric TB treatment achieved a statistically significant 44% reduction in 8-week mortality among seriously ill HIV-positive inpatients with WHO’s ‘danger signs’ (Katagira 2016).

Clearly, access to better, more reliable diagnostics would lead to more expeditious TB treatment for seriously ill individuals with co-infection, but it is hoped that, until such tools become available, use of this algorithm could minimise delay in TB treatment initiation and prevent early mortality. In the meantime, programmes are urged to “adopt rapid TB diagnostic tools (Xpert MTB/RIF and LF-LAM) to increase earlier diagnoses of TB,” concluded Hamada.

Abstract 1
Introduction: Despite significant progress in improving access to antiretroviral therapy over the past decade, substantial numbers of people living with HIV (PLHIV) in all regions continue to experience severe illness and require hospitalization. We undertook a global review assessing the proportion of hospitalizations and in-hospital deaths because of tuberculosis (TB) in PLHIV.
Methods: Seven databases were searched to identify studies reporting causes of hospitalizations among PLHIV from 1 January 2007 to 31 January 2015 irrespective of age, geographical region or language. The proportion of hospitalizations and in-hospital mortality attributable to TB was estimated using random effects meta-analysis.
Results: From an initial screen of 9049 records, 66 studies were identified, providing data on 35,845 adults and 2792 children across 42 countries. Overall, 17.7% (95% CI 16.0 to 20.2%) of all adult hospitalizations were because of TB, making it the leading cause of hospitalization overall; the proportion of adult hospitalizations because of TB exceeded 10% in all regions except the European region. Of all paediatric hospitalizations, 10.8% (95% CI 7.6 to 13.9%) were because of TB. There was insufficient data among children for analysis by region. In-hospital mortality attributable to TB was 24.9% (95% CI 19.0 to 30.8%) among adults and 30.1% (95% CI 11.2 to 48.9%) among children.
Discussion: TB remains a leading cause of hospitalization and in-hospital death among adults and children living with HIV worldwide.

Ford N, Matteelli A, Shubber Z, Hermans S, Meintjes G, Grinsztejn B, Waldrop G, Kranzer K, Doherty M, Getahun H

Abstract 2
Objectives: Tuberculosis (TB) is estimated to be the leading cause of HIV-related deaths globally. However, since HIV-associated TB frequently remains unascertained, we systematically reviewed autopsy studies to determine the true burden of TB at death.
Methods: We systematically searched Medline and Embase databases (to end 2013) for literature reporting on health facility-based autopsy studies of HIV-infected adults and/or children in resource-limited settings. Using forest plots and random-effects meta-analysis, we summarized the TB prevalence found at autopsy and used meta-regression to explore variables associated with autopsy TB prevalence.
Results: We included 36 eligible studies, reporting on 3237 autopsies. Autopsy TB prevalence was extremely heterogeneous (range 0-64.4%), but was markedly higher in adults [pooled prevalence 39.7%, 95% confidence interval (CI) 32.4-47.0%] compared to children (pooled prevalence 4.5%, 95% CI 1.7-7.4%). Post-mortem TB prevalence varied by world region, with pooled estimates in adults of 63.2% (95% CI 57.7-68.7%) in South Asia (n = 2 studies); 43.2% (95% CI 38.0-48.3) in sub-Saharan Africa (n = 9 studies); and 27.1% (95% CI 16.0-38.1%) in the Americas (n = 5 studies). Autopsy prevalence positively correlated with contemporary estimates of national TB prevalence. TB in adults was disseminated in 87.9% (82.2-93.7%) of cases and was considered the cause of death in 91.4% (95% CI 85.8-97.0%) of TB cases. Overall, TB was the cause of death in 37.2% (95% CI 25.7-48.7%) of adult HIV/AIDS-related deaths. TB remained undiagnosed at death in 45.8% (95% CI 32.6-59.1%) of TB cases.
Conclusions: In resource-limited settings, TB accounts for approximately 40% of facility-based HIV/AIDS-related adult deaths. Almost half of this disease remains undiagnosed at the time of death. These findings highlight the critical need to improve the prevention, diagnosis and treatment of HIV-associated TB globally.

Gupta RK, Lucas SB, Fielding KL, Lawn SD

Abstract 3
The public sector scale-up of antiretroviral therapy (ART) in South Africa commenced in 2004. We aimed to describe the hospital-level disease burden and factors contributing to morbidity and mortality among hospitalized HIV-positive patients in the era of widespread ART availability. Between June 2012 and October 2013, unselected patients admitted to medical wards at a public sector district hospital in Cape Town were enrolled in this cross-sectional study with prospective follow-up. HIV testing was systematically offered and HIV-infected patients were systematically screened for TB. The spectrum of admission diagnoses among HIV-positive patients was documented, vital status at 90 and 180 days ascertained and factors independently associated with death determined. Among 1018 medical admissions, HIV status was ascertained in 99.5%: 60.1% (n = 609) were HIV-positive and 96.1% (n = 585) were enrolled. Of these, 84.4% were aware of their HIV-positive status before admission. ART status was naive in 35.7%, current in 45.0%, and interrupted in 19.3%. The most frequent primary clinical diagnoses were newly diagnosed TB (n = 196, 33.5%), other bacterial infection (n = 100, 17.1%), and acquired immunodeficiency syndrome (AIDS)-defining illnesses other than TB (n = 64, 10.9%). By 90 days follow-up, 175 (29.9%) required readmission and 78 (13.3%) died. Commonest causes of death were TB (37.2%) and other AIDS-defining illnesses (24.4%). Independent predictors of mortality were AIDS-defining illnesses other than TB, low hemoglobin, and impaired renal function. HIV still accounts for nearly two-thirds of medical admissions in this South African hospital and is associated with high mortality. Strategies to improve linkage to care, ART adherence/retention and TB prevention are key to reducing HIV-related hospitalizations in this setting.

Meintjes G, Kerkhoff AD, Burton R, Schutz C, Boulle A, Van Wyk G, Blumenthal L, Nicol MP, Lawn SD

Abstract 4
Rationale: In 2007, World Health Organization (WHO) issued emergency recommendations on empiric treatment of sputum acid-fast bacillus smear-negative patients with possible tuberculosis (TB) in HIV-prevalent areas, and called for operational research to evaluate their effectiveness. We sought to determine if early, empiric TB treatment of possible TB patients with abnormal chest radiography or severe illness as suggested by the 2007 WHO guidelines, is associated with improved survival.
Methods: We prospectively enrolled consecutive HIV-seropositive inpatients at Mulago Hospital in Kampala, Uganda, from 2007 to 2011 with cough for ≥2 weeks. We retrospectively examined the effect of empiric TB treatment before discharge on 8-week survival among those with and without a WHO-defined “danger sign,” including fever >39°C, tachycardia >120 beats per minute, or tachypnea >30 breaths per minute. We modeled the interaction between empiric TB treatment and danger signs, and their combined effect on 8-week survival, and adjusted for relevant covariates.
Results: Among 631 sputum smear-negative patients, 322 (51%) had danger signs. Cumulative 8-week survival of patients with danger signs was significantly higher with empiric TB treatment (80%) than without treatment (64%, P < 0.001). After adjusting for duration of cough and concurrent hypoxemia, patients with danger signs who received empiric TB treatment had a 44% reduction in 8-week mortality (risk ratio 0.56, 95% confidence interval: 0.34-0.91, P = 0.020).
Conclusions: Empiric TB treatment of HIV-seropositive, smear-negative, presumed pulmonary TB patients with 1 or more danger signs is associated with improved 8-week survival. Enhanced implementation of the 2007 WHO empiric treatment recommendations should be encouraged whenever and wherever rapid and highly sensitive diagnostic tests for TB are unavailable.

Katagira W, Walter ND, Den Boon S, Kalema N, Ayakaka I, Vittinghoff E, Worodria W, Cattamanchi A, Huang L, Davis JL

Aidsmap material
Journal of the International AIDS Society abstract
AIDS abstract
AIDS2016 session
Medicine 94 abstract
Journal of Acquired Immune Deficiencies abstract
WHO guidelines

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